Antiviral Effects of ABMA and DABMA against Influenza Virus In Vitro and In Vivo via Regulating the Endolysosomal Pathway and Autophagy.

Abstract

Influenza virus is an acute and highly contagious respiratory pathogen that causes great concern to public health and for which there is a need for extensive drug discovery. The small chemical compound ABMA and its analog DABMA, containing an adamantane or a dimethyl-adamantane group, respectively, have been demonstrated to inhibit multiple toxins (diphtheria toxin, Clostridium difficile toxin B, Clostridium sordellii lethal toxin) and viruses (Ebola, rabies virus, HSV-2) by acting on the host's vesicle trafficking. Here, we showed that ABMA and DABMA have antiviral effects against both amantadine-sensitive influenza virus subtypes (H1N1 and H3N2), amantadine-resistant subtypes (H3N2), and influenza B virus with EC50 values ranging from 2.83 to 7.36 µM (ABMA) and 1.82 to 6.73 µM (DABMA), respectively. ABMA and DABMA inhibited the replication of influenza virus genomic RNA and protein synthesis by interfering with the entry stage of the virus. Molecular docking evaluation together with activity against amantadine-resistant influenza virus strains suggested that ABMA and DABMA were not acting as M2 ion channel blockers. Subsequently, we found that early internalized H1N1 virions were retained in accumulated late endosome compartments after ABMA treatment. Additionally, ABMA disrupted the early stages of the H1N1 life cycle or viral RNA synthesis by interfering with autophagy. ABMA and DABMA protected mice from an intranasal H1N1 challenge with an improved survival rate of 67%. The present study suggests that ABMA and DABMA are potential antiviral leads for the development of a host-directed treatment against influenza virus infection.

• Authors: Hongtao Liu, Chunlai Jiang, Yu Wu, Min Wu, Jiaxin Wu, Guanshu Zhao, Jie Sun, Xinyu Huang, Jiemin Li, Rui Sheng, Julien Barbier, Jean-Christophe Cintrat, Daniel Gillet, Weiheng Su
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 7 (Apr 01 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35409297 (Publication Type: Journal Article)

Chemical References

• 4-dimethylaminoazobenzene-4'-N-maleimide
• Antiviral Agents
• p-Dimethylaminoazobenzene
• Amantadine
• Adamantane

Topics

• Adamantane
• Amantadine (pharmacology)
• Animals
• Antiviral Agents (chemistry, pharmacology)
• Autophagy
• Endosomes
• Influenza A Virus, H1N1 Subtype (genetics)
• Influenza A Virus, H3N2 Subtype
• Mice
• Molecular Docking Simulation
• p-Dimethylaminoazobenzene (analogs & derivatives)